This invention relates to a process for producing substituted pyrroles, especially pyrrole-2-acetic acids and derivative compounds thereof. More particularly, the process of this invention is concerned with processes which produce 1,4-diloweralkyl-3-lower-alkoxycarbonyl-pyrrole-2-acetate which is a useful intermediate for analgesic and anti-inflammatory pharmaceutical compounds.
It has been found difficult in the past to substitute pyrrole rings, which already contain substituents at other positions on the rings, at the 4-position because of steric hindrance and ring deactivation. Thus, Carson, U.S. Pat. Nos. 3,752,826 and 3,865,840, teach the preparation of certain 4-substituted 5-aroyl-pyrrole alkanoic acids and the corresponding salts, esters, nitriles, amides, and substituted amides thereof represented by the formulas: ##STR1## wherein: Ar represents a member selected from the group consisting of phenyl, monosubstituted phenyl and polysubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl and lower alkoxy;
Ar.sub.1 represents a member selected from the group consisting of phenyl, thienyl, 5-methylthienyl, monosubstituted phenyl and polysubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, lower alkoxy, nitro, amino, cyano, and methylthio; PA0 R represents a member selected from the group consisting of COOH, COO-(lower alkyl), CONH.sub.2, CONH-(lower alkyl) and CON-(lower alkyl).sub.2 ; PA0 R.sub.1 represents lower alkyl; PA0 R.sub.2 represents a member selected from the group consisting of hydrogen and lower alkyl, provided that when said Ar, is a member of the group consisting of nitrosubstituted phenyl, then, with regard to Formula III, R.sub.2 is hydrogen; PA0 Me is methyl; PA0 (a) adding said chloromethylloweralkyl ketone to a pre-mixed cooled solution of said loweralkylamine and said dicarboxylate in a suitable solvent with reaction at below 60.degree. C., and PA0 (b) heating the resulant reaction mixture to from about 70.degree. to about 100.degree. C. for a period sufficient to dehydrate the dihydroxy pyrrolidine intermediate in said resultant reaction mixture and produce the desired loweralkyl 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate.
and the non-toxic, therapeutically acceptable salts of such acids, such as are obtained from the appropriate organic and inorganic bases. According to Carson, supra, the 4-substituted 5-aroylpyrrole alkanoic acids must be obtained by condensation of the appropriate 1-aryl-1,2,3-butanetrione-2-oxime and an appropriate dialkyl acetonedicarboxylate as starting materials to provide the corresponding ring closed pyrrole, alkyl 5-aroyl-3-alkoxycarbonyl-4-methylpyrrole-2-acetate; or by condensation of an appropriate chloromethyl loweralkyl ketone added to a mixture of an appropriate di-loweralkyl acetonedicarboxylate, preferably the diethyl ester and a loweralkyl amine to provide the ring-closed pyrrole, alkyl 1,4-diloweralkyl-3-alkoxy-carbonyl pyrrole-2-acetate. These pyrrole intermediates are then treated as disclosed in U.S. Pat. Nos. 3,752,826 and 3,865,840 to obtain the desired 5-aroyl-4-lower alkyl-pyrrole-2-alkanoic acids and acid derivatives thereof useful as anti-inflammatory agents.
The condensation of chloromethylketone, ammonia and hydroxy crotonic acid alkylester through an anticrotonic acid ester is taught by Fischer and Orth, Die Chemie Des Pyrroles, pp. 5-6 and 233-234, Edward Brothers, Inc., Ann Arbor, Mich., 1943. However, neither the 4-alkyl-substituent nor the diester functionality are disclosed in this reference.
Another pyrrole ring-closure synthesis, known as the Hantzsch pyrrole synthesis, teaches the interaction of alphachloro-aldehydes or ketones with beta-ketoesters and ammonia or amines to give pyrroles, Gowan and Wheeler, Name Index of Organic Reactions, p. 116, Longmans, Green and Co., Ltd. New York, N.Y., 1960.
In a similar manner, there is taught the reaction of chloroacetone with a salt produced from reaction of methyl amine and diethyl acetone dicarboxylate to give a 4-methylpyrrole, Jones and Bean, The Chemistry of Pyrroles, p. 59, 104, Academic Press Inc., New York, 1977. Also, the pyrrole synthesis from chloromethyl ketones and beta-ketocarboxylic esters with ammonia or amines is known, Krauch and Kunz, Organic Name Reactions, p. 211, John Wiley and Sons, Inc., New York, 1964. However, such teachings either fail to suggest the possibility of the pyrrole diester compounds or teach no more than Carson, supra, and are based thereon.
Specifically pertinent to the improved process of this invention, U.S. Pat. Nos. 3,752,826 and 3,865,840 teach that after reaction of, for example, aqueous methylamine with diethyl acetone-dicarboxylate and then adding chloroacetone at a temperature below 60.degree. C. for a period of two hours, the resultant reaction mixture is poured into ice-hydrochloric acid. The acidification acts to dehydrate the intermediate dihydroxy pyrrolidine to the desired pyrrole. However, it was discovered that prior to acidification the intermediate reaction mixture contained only minimal amounts of the desired 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetic acid ester when analyzed by NMR. In contrast, upon analysis by vapor phase chromatograph of an aliquot of the same sample, a major amount of the desired ester was shown. This indicated heating in the chromatograph injection port at about 100.degree. C. was responsible.